# Molecular mechanisms of Progranulin in Neurodegeneration

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $385,499

## Abstract

Project Summary
 Frontotemporal degeneration (FTD) and Alzheimer’s disease (AD) are two of the most common causes
of dementia, share overlapping pathologies, are huge health burdens, and are incurable. This proposal focuses
on elucidating how loss of progranulin (PGRN), and its mature products the granulins, drive neurodegeneration
and lysosomal dysfunction associated with FTD and AD. PGRN is a secreted protein composed of 7.5 tandem
domains that are cleaved into 6kDa granulin proteins (GRNs), through a poorly defined pathway. Genetic
variants and loss-of-function mutations in the progranulin gene (Grn), reduce the production of the progranulin
(PGRN) protein and increase the risk of AD and cause FTD, respectively. Converging evidence suggest that
decreased levels of PGRN/granulins induce lysosomal dysfunction leading to neuroinflammation and
degeneration through an unknown mechanism. Based on our published work and new data, we propose that
granulins are the functional unit of PGRN and are produced in the endo-lysosomal pathway. We find
PGRN is trafficked to the lysosome and processed into stable granulins in multiple tissues and cells. Clinically,
PGRN and granulins are equally decreased in iPSC-derived neurons and brain tissue from FTD-GRN carriers.
Further, expression of the FTD-risk-factor TMEM106B reduces granulins. Finally, extracellular granulin can
rescue lysosomal defects in Grn KO mouse fibroblasts, providing strong evidence that granulins facilitate
lysosome function. Our findings fit into the larger narrative that lysosome-autophagy dysfunction is a critical
pathogenic mechanism in FTD and AD. Our preliminary data lead us to propose the hypothesis that PGRN is
trafficked to the lysosome and processed into mature, functional granulins that mediate lysosomal
homeostasis and neuroprotection. Successful completion of the following specific aims will advance the
neurodegeneration field by providing mechanism-based rationale for testing granulins as a novel therapy for
FTD and AD. We will 1) delineate the molecular pathways that traffic PGRN to the lysosome, 2) determine the
molecular mechanisms of granulin production and function in the lysosome, and 3) determine the in vivo role of
PGRN and granulins in lysosome dysfunction and neurodegeneration. Completion of the proposed studies will
enable us to critically evaluate the paradigm-shifting hypothesis that granulins are lysosomal, functional, and
neuroprotective. In doing so, we will uncover why decreased levels of PGRN lead to FTD, AD, or NCL and a
new approach to treat diseases caused by decreased PGRN.

## Key facts

- **NIH application ID:** 10112970
- **Project number:** 5R01NS105971-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** THOMAS L KUKAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,499
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112970

## Citation

> US National Institutes of Health, RePORTER application 10112970, Molecular mechanisms of Progranulin in Neurodegeneration (5R01NS105971-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10112970. Licensed CC0.

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